Stereoselective syntheses

ABSTRACT

The present invention relates to the synthesis of chiral amino acids and to novel ferrocene-substituted oxazolidinone derivatives useful in such syntheses.

This application is a 371 of PCT/GB95/02484 filed Oct. 20, 1995

This invention relates to the synthesis of chiral amino acids and tonovel ferrocene-substituted oxazolidinone derivatives useful in suchsyntheses.

As is well known, the synthesis of chiral molecules in substantiallyenantiomerically pure form (which term is used herein to denotecompounds containing at least 80%, advantageously at least 90%, andpreferably at least 95% of a desired enantiomer) is of great importance,for example to the pharmaceutical industry, and much attention has beengiven to stereoselective syntheses which facilitate the preparation ofsuch chiral compounds.

One area of interest within this general field is the stereoselectivereplacement of a hydrogen atom from the α-carbon atom of an α-amino acid(either natural or unnatural), e.g. by electrophilic substitution, toyield a chiral α-substituted α-amino acid. Products so obtained may, forexample, be useful directly in the manufacture of pharmaceuticals or inpreparing chiral auxiliaries of use in the synthesis of chiral molecules(see, for example, our International Patent Publication No. WO95/18112). Existing methods for the preparation of such substitutedα-amino acids either lead to products with insufficient enantiomericpurity, e.g. as a result of racemisation where the α-amino acid startingmaterial is a substantially enantiomerically pure chiral compound, orgive unacceptably low yields.

The present invention is based on our finding that highly efficientstereoselective substitution at the α-carbon atom of an α-amino acid maybe effected if the α-amino acid or a carboxylate salt thereof is reactedwith ferrocene carboxaldehyde or a derivative thereof to yield aSchiff's base which is then cyclised, e.g. by reaction with an acylatingagent, to yield a chiral ferrocenyl-substituted 1,3-oxazolidin-5-one;the chirality of this molecule may derive from use of a chiral α-aminoacid or, where glycine is chosen as the α-amino acid, from elsewhere inthe molecule, e.g. by appropriate substitution of the ferrocene ringsystem or by use of a chiral acylating agent. We have found that suchchiral oxazolidinones may be obtained in diastereomerically pure formand in substantially quantitative yield as the exclusively formedproduct; they may therefore be subjected to further reaction, e.g. tostereoselective electrophilic substitution at the α-carbon atom of theα-amino acid, without any intermediate separation step. Following suchsubstitution the oxazolidinone may be cleaved to yield substantiallyenantiomerically pure α-substituted α-amino acid and to regenerate theferrocene carboxaldehyde or derivative thereof.

Thus according to one aspect of the present invention there is provideduse of ferrocene carboxaldehyde or a derivative thereof in thepreparation of a substantially enantiomerically pure α-substitutedα-amino acid, for example by stereoselective electrophilic substitutionat the α-carbon atom thereof.

Viewed from another aspect the invention provides a process whichcomprises the steps:

(i) reacting an α-amino acid having at least one α-carbon-attachedhydrogen atom or a carboxylate salt thereof (hereinafter referred to asthe α-amino acid starting material) with ferrocene carboxaldehyde or aderivative thereof so as to yield a corresponding Schiff's base;

(ii) cyclising said Schiff's base to yield a chiral N-protected2-ferrocenyl-substituted 1,3-oxazolidin-5-one (hereinafter referred toas the first chiral oxazolidinone);

(iii) subjecting said first chiral oxazolidinone to electrophilicsubstitution whereby said α-carbon-attached hydrogen atom is replaced bya substituent to yield a substantially enantiomerically pure secondchiral oxazolidinone; and

(iv) subjecting said second chiral oxazolidinone to ring cleavage so asto generate a substantially enantiomerically pure α-substituted α-aminoacid (hereinafter referred to as the substituted α-amino acid product).

The above described process will now be described in greater detail withregard to the individual process steps, as follows:

Step (i)

The α-amino acid starting material may, for example, be a compound ofgeneral formula (I) ##STR1## (where R represents a hydrogen atom or anorganic group and X represents a hydrogen atom or a cation). It will beappreciated that when R is other than hydrogen the compound (I) will bechiral; it will normally be desirable to employ such starting materialsin substantially enantiomerically pure form.

Where R represents an organic group this may, for example, be analiphatic, cycloaliphatic or araliphatic group, e.g. containing up to 20carbon atoms and optionally carrying one or more substituents. R maythus, for example, represent a group selected from C₁₋₁₀ alkyl (e.g. asin methyl, ethyl, propyl or butyl groups); C₂₋₁₀ alkenyl (e.g. vinyl orpropenyl); C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl (e.g. cyclopentylmethyl); C₆₋₁₂carbocyclic aryl-C₁₋₄ alkyl (e.g. benzyl); heterocyclic aryl-C₁₋₄ alkyl(e.g. wherein the heterocyclic group comprises one or more 5- and/or6-membered rings and contains at least one heteroatom selected from O, Nand S); and substituted versions of any of the preceding groups, forexample carrying one or more amino, carbamoyl, carboxyl, guanidino,hydroxyl, alkoxy (e.g. methoxy), mercapto or methylthio groups,protected as necessary.

Where X represents a cation this may be inorganic or organic.Representative inorganic cations include those derived from alkali andalkaline earth metals, for example sodium or potassium. Representativeorganic cations include those derived from strongly basic amines, forexamples tertiary amines such as trialkylamines.

One useful class of starting materials (I) comprises compounds in whichR is the α-substituent of a natural α-amino acid or an enantiomerthereof. Preferred R groups thus include methyl, isopropyl, isobutyl,sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, carboxymethyl,2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(methylthio)ethyl,4-aminobutyl, benzyl, p-hydroxybenzyl, indol-3-ylmethyl,imidazol-4-ylmethyl or 3-guanidinopropyl. It will be appreciated that itmay be necessary to protect reactive substituents such as amino,carboxyl, hydroxyl or thiol groups in such R groups, for example usingappropriate blocking groups, e.g. such as are known in the art, duringthe course of processing of compounds (I) in accordance with theinvention.

Derivatives of ferrocene carboxaldehyde which may be used in accordancewith the invention carry one or more further ring substituents inaddition to the carboxaldehyde group. The ferrocene carboxaldehyde orderivative thereof may therefore, for example, be a compound of generalformula (II) ##STR2## (where m is 0 or an integer of 1-4, n is 0 or aninteger of 1-5, and R^(a) and R^(b) represent substituting atoms orgroups). It will be appreciated that where the compound (II) containsmore than one of R^(a) and/or R^(b) these may represent different atomsor groups.

R^(a) and R^(b) may, for example, be selected from lower (e.g. C₁₋₆)alkyl (e.g. methyl, ethyl, propyl or butyl groups, such as t-butyl),lower alkoxy (e.g. methoxy or ethoxy), lower alkylthio (e.g.methylthio), lower alkylsulphonyl (e.g. methylsulphonyl), lower alkanoyl(e.g. acetyl), lower alkanoyloxy (e.g. acetoxy), lower alkoxycarbonyl(e.g. methoxycarbonyl), disubstituted amino (e.g. di(lower alkyl)aminosuch as dimethylamino), disubstituted aminoalkyl (e.g. di(loweralkyl)amino lower alkyl such as dimethylaminomethyl or1-dimethylaminoethyl), lower alkanoylamino (e.g. acetamido), C₆₋₁₂aryl-C₁₋₄ alkyl (e.g. benzyl or phenethyl), C₆₋₂₀ aryl (e.g. phenyl ornaphthyl), carbamoyl, sulphamoyl, nitro and halo (e.g. chloro, bromo oriodo).

One of R^(b) may advantageously be a carboxaldehyde group, therebypermitting one mole of the ferrocene carboxaldehyde derivative to reactwith two moles of the α-amino acid starting material.

The α-amino acid starting material and ferrocene carboxaldehyde orderivative thereof may be reacted under any appropriate conditions, forexample at ambient temperature in an appropriate mutual solvent, forexample an alcohol such as ethanol. Stoichiometric amounts of the tworeagents are preferably employed.

Where starting materials of formulae (I) and (II) are employed, theSchiff's base product from this reaction step may be represented bygeneral formula (III) ##STR3## (where R, R^(a), R^(b), X, m and n are ashereinbefore defined). Such compounds are novel and constitute a featureof the present invention. It will be appreciated that, where one ofR^(b) in general formula (II) represents a carboxaldehyde group thiswill become a group --C═N--CH(R)--COOX in general formula (III).

Step (ii)

Cyclisation of the Schiff's base may conveniently be effected byreaction with a compound serving to introduce an N-protecting group atthe imine nitrogen atom, e.g. to yield a compound of general formula(IV) ##STR4## (where R, R^(a), R^(b), m and n are as hereinbeforedefined and R¹ represents an N-protecting group) in the case ofcyclisation of a compound of general formula (III). Such compounds arenovel and constitute a feature of the present invention. It will beappreciated that when one of R^(b) in general formula (III) represents agroup --C═N--CH(R)--COOX this will become an oxazolidinone group ingeneral formula (IV).

An important advantage of the invention is the diastereomeric purity ofproducts such as compounds of general formula (IV) formed in thisreaction step.

Representative N-protecting groups which may be used in the cyclisationstep include lower alkanoyl such as acetyl, haloacetyl (e.g.trichloroacetyl), propionyl, isobutyryl or pivaloyl, e.g. introduced byreaction with an appropriate acylating agent, for example an acidanhydride or an acyl halide such as the chloride; lower alkoxycarbonylsuch as t-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl, e.g.introduced by reaction with an appropriate haloformate such as thechloroformate; sulphonyl, including lower alkyl sulphonyl such astrifluoromethanesulphonyl and aryl sulphonyl such as p-toluenesulphonyl,e.g. introduced by reaction with an appropriate sulphonyl halide such asthe chloride; and silyl, for example tri(lower alkyl) silyl such astrimethylsilyl, triisopropylsilyl or t-butyldimethylsilyl, e.g.introduced by reaction with an appropriate silyl halide such as thechloride. As described hereinafter it may be desirable to introduce achiral N-protecting group such as camphanyl or camphasulphonyl, e.g. byreaction with the corresponding chlorides.

R¹ may if desired be derived from the C-terminal of a polypeptidewhereby a new polypeptide may be obtained by hydrolysis of the compound(IV).

The cyclisation reaction may be carried out under any appropriateconditions, for example at ambient or reduced temperature in anappropriate mutual solvent, for example a halogenated hydrocarbon suchas dichloromethane in the case of reaction with an acylating agent suchas an acyl halide. Stoichiometric amounts of the two reagents arepreferably employed.

Step (iii)

Compounds of general formula (IV) where R is other than hydrogen possesschirality at the 4-position of the oxazolidinone ring and will undergostereospecific electrophilic substitution at this position to yield asubstantially enantiomerically pure second chiral oxazolidinone.

Compounds of general formula (IV) where R is hydrogen, i.e. where theα-amino acid starting material is glycine or a carboxylate salt thereof,do not possess chirality at this position, and in such cases it will benecessary for there to be chirality elsewhere in the molecule so as tocontrol the direction of electrophilic substitution at the 4-position ofthe oxazolidinone ring and ensure formation of a substantiallyenantiomerically pure second chiral oxazolidinone. Thus, for example, anasymmetric pattern of substituents R^(a) may be present, preferably inthe form of a single substituent ortho to the carboxaldehyde group ingeneral formula (II). Where in this embodiment one of R^(b) in generalformula (II) represents a carboxaldehyde group a similar single orthosubstituent is preferably present, its position being such that the mesoconfiguration is avoided. It may be advantageous in such cases for theortho substituent to be relatively bulky and/or chelating in order toenhance its directing effect. Alternatively, as noted above, chiralitymay be imparted to a compound (IV) in which R is hydrogen by thepresence of a chiral R¹ group.

Sources of electrophiles which may be used in this reaction stepinclude, for example, aliphatic and araliphatic halides, epoxides,aldehydes and ketones. The oxazolidinone starting material is preferablyreacted with a strong base capable of promoting enolisation of the5-keto group (e.g. a Group IA, IIA or IIIA metal alkyl, metal alkylhalide, metal alkyl trifluoroacetate or metal alkylamine such as lithiumdiisopropylamide), either during or, more preferably, before reactionwith the source of electrophile. The reactions with the base andelectrophile are preferably carried out in an inert solvent, e.g. acyclic ether such as tetrahydrofuran, at a temperature of 0° C. or less,e.g. -78° C., if desired under an inert atmosphere, e.g. of nitrogen.

In the case of reaction of a compound of general formula (IV) theelectrophilically substituted product may be represented by generalformula (V) ##STR5## (where R, R¹, R^(a), R^(b), m and n are ashereinbefore defined, R² represents an organic group which is theresidue of an electrophile, and the asterisk denotes that theconfiguration of R and R² is such that the compound is in substantiallyenantiomerically pure form). Such compounds are novel and constitute afeature of the present invention. It will be appreciated that where oneof R^(b) in general formula (IV) represents an oxazolidinone group thiswill become a corresponding substituted oxazolidinone group in generalformula (V).

Representative R² groups in the above general formula (V) includealiphatic and araliphatic groups, e.g. containing up to 20 carbon atomsand optionally carrying one or more substituents. R² may thus, forexample, represent a group selected from optionally substituted C₁₋₁₀alkyl (e.g. as in methyl, cyanomethyl, ethyl, propyl or butyl groups);optionally substituted C₂₋₁₀ alkenyl (e.g. allyl or crotyl); optionallysubstituted C₆₋₁₂ carbocyclic aryl-C₁₋₄ alkyl (e.g. benzyl,2-methylbenzyl or naphthylmethyl such as naphth-2-ylmethyl); optionallysubstituted heterocyclic aryl-C₁₋₄ alkyl (e.g. wherein the heterocyclicgroup comprises one or more 5- and/or 6-membered rings and contains atleast one heteroatom selected from O, N, and S, for example as inN-protected indolylmethyl such as 1-t-butoxycarbonylindol-3-ylmethyl);and optionally substituted C₆₋₁₂ carbocyclic aryl-C₂₋₄ alkenyl andheterocyclic aryl-C₂₋₄ alkenyl groups (e.g. cinnamyl).

Step (iv)

Ring cleavage of the second chiral oxazolidinone may conveniently beeffected by acid or base catalysed hydrolysis, e.g. using an acidic orbasic ion exchange catalyst resin or an inorganic acid or base, forexample an alkali metal hydroxide such as lithium hydroxide. Suchhydrolytic cleavage may conveniently be carried out in anaqueous/organic solvent system such as aqueous acetone.

It will be appreciated that the reaction conditions for the ringcleavage and the nature of the N-protecting group at the 3-position ofthe oxazolidinone ring may advantageously be chosen so that ringcleavage is accompanied by N-deprotection, e.g. leading to formation ofa substituted α-amino acid product of general formula (VI) ##STR6##(where R, R², X and the meaning of the asterisk are as hereinbeforedefined) or an acid addition salt thereof in the case of cleavage of acompound of general formula (V).

The reaction conditions are preferably also such that the ferrocenecarboxaldehyde or derivative thereof is regenerated.

The following non-limitative examples serve to illustrate the invention.

EXPERIMENTAL TECHNIQUES

Melting points (m.p.) were obtained using a Thermogalen™ III meltingpoint apparatus and are uncorrected.

Optical rotations were measured with a Perkin-Elmer 241 polarimeter witha thermally jacketted 10 cm cell at approximately 20° C. and are givenin units of 10⁻¹ deg cm² g⁻¹. Concentrations (c) are given in g/100 ml.

Infrared (IR) spectra were recorded as thin films between sodiumchloride plates, as potassium bromide discs or in chloroform solution ona Perkin-Elmer 1750 Fourier Transform spectrometer. Absorptions arereported in wavenumbers (cm⁻¹). The following abbreviations are used: w,weak; m, medium; s, strong and br, broad.

Proton magnetic resonance spectra (¹ H NMR) were recorded at 200 MHz ona Varian Gemini 200 or Bruker AC200 spectrometer, at 300 MHZ on a BrukerWH300 and at 500 MHz on a Bruker AM500 spectrometer. For ¹ H NMRrecorded in CDCl₃, CH₃ OD and D₂ O, chemical shifts (δ_(H)) are quotedin parts per million (p.p.m.) and are referenced to the residual solventpeak. The following abbreviations are used: s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet and br, broad. Coupling constants (J)were recorded in Hertz to the nearest 0.5 Hz.

Carbon magnetic resonance spectra (¹³ C NMR) were recorded at 50.31 MHzon a Varian Gemini 200 or Bruker AC200 spectrometer and at 125.77 MHz ona Bruker AMX500 spectrometer using DEPT editing. Chemical shifts (δ_(c))are quoted in p.p.m. and referenced to CDCl₃ and CH₃ OD unless otherwisestated. Spectra recorded in D₂ O are referenced to internal 1,4-dioxane.

Diastereomeric excesses (d.e.) were determined by peak integration ofthe crude reaction products' ¹ H and ¹³ C NMR spectra. Enantiomericexcesses (e.e.) were obtained using (R)-(-)- or(S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol as a chiral shift reagenton crude reaction samples.

Low resolution mass spectra (m/z) were recorded on a VG Micromass ZAB 1F(CI/DCI/FAB), a VG Masslab 20-250 (CI/DCI) or a VG BIO Q (electrospray)spectrometer, with only molecular ions (M⁺), fragments from molecularions and major peaks being reported.

Column chromatography was performed on silicagel (Kiesel 60) orAmberlyst-15 resin. TLC was carried out with precoated silicagel 60F-254 plates.

Anhydrous dichloromethane was obtained by distillation from calciumhydride under nitrogen. Anhydrous diethyl ether and anhydroustetrahydrofuran were obtained by distillation from sodium/benzophenoneketyl under nitrogen. Petroleum refers to light petroleum (b.p. 40°-60°C.), redistilled before use. Ferrocenecarboxaldehyde andD,L-α-methylphenylalanine were purchased from Aldrich, the former beingpurified by flash chromatography (silicagel-diethyl ether) before use.Pivaloyl chloride was purified by bubbling nitrogen into the liquid andby distillation from calcium chloride and alumina (under nitrogen).

All reactions were performed under an atmosphere of dry nitrogen.

EXAMPLE 1

Ferrocenecarboxaldehyde sodium L-alaninate imine

Aqueous sodium hydroxide (11.2 mmol in 11 ml of water) was added toL-alanine (1.0 g, 11.22 mmol) and stirred for several minutes at roomtemperature. The solvent was removed in vacuo and the residue dried at60° C. under high vacuum overnight. 4 Å molecular sieves,ferrocenecarboxaldehyde (11.78 mmol, 2.52 g) and absolute ethanol (50ml) were added to the alaninate and stirred for 5 hours; the course ofthe reaction can be followed by IR. The molecular sieves were separatedby filtration, the filtrate concentrated on a vacuum line and a redsolid was obtained. Pentane (50 ml) was added and the mixture wasstirred until a suspension was formed. This was filtered through asinter and the residue was washed with pentane and dried under vacuum togive the title compound as a yellow-orange solid (3.28 g, 950%); ν_(max)(KBr disc) 1641 s (C═N) and 1591 (CO₂ ⁻) cm⁻¹. The imine rapidlyundergoes hydrolysis on silica or in the presence of water.

EXAMPLE 2 (2S,4S)-2-Ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

4 Å Molecular sieves and dichloromethane (90 ml) were added to theproduct from Example 1 (3 g, 9.77 mmol), the mixture was cooled to -18°C., then recently distilled pivaloyl chloride (1.21 ml, 9.77 mmol)dissolved in dichloromethane (10 ml) was added dropwise. The resultingmixture was stirred overnight while being allowed to warm up to roomtemperature. The reaction mixture was filtered, and the filtrate wasconcentrated on a vacuum line (in the absence of heat to avoidracemisation taking place). Several portions of diethyl. ether wereadded and then quickly passed through a sinter containing silica andcelite. The ether was removed on a vacuum line without heating to givethe title compound (3.42 g, 95%) as yellow crystals with >98% d.e. (>98%e.e. for the major diastereoisomer); m.p. 105° C.; R_(f) 0.38(petroleum-diethyl ether; 7:3); α!_(D) ²⁵ +21.5 (c 1.0, CHCl₃); ν_(max)(KBr disc) 3097 (HC═C), 1796 (OC═O) and 1643 (NC═O)cm⁻¹ ; δ_(H) (200MHz; C₆ D₆) 0.90 (9H, s, C(CH₃)₃), 1.26 (3H, d, J 7 Hz, CHCH₃),3.86-3.91 (2H, m, Cp), 4.07 (5H, s, Cp'), 4.11-4.12 (1H, m, Cp), 4.23(1H, q, J 7 Hz, CHCH₃), 4.70-4.71 (1H, m, Cp) and 7.10 (1H, S, OCHN);δ_(H) (200 MHz, CDCl₃) 1.27 (9H, s, C(CH₃)₃), 1.56 (3H, d, J 7 Hz,CHCH₃), 4.18-4.23 (3H, m, Cp), 4.25 (5H, s, Cp'), 4.59-4.61 (1H, m, Cp),4.64 (1H, q, J 7 Hz, CHCH₃) and 7.07 (1H, s, OCH); δ_(c) (50.3 MHz;CDCl₃) 20.0 (CHCH₃), 28.1 (C(CH₃)₃), 39.9 (C₃)₃), 52.0 (CHCH₃), 65.3,67.8, 68.4, 69.2, 85.0 (9×CH in Cp and Cp'), 88.7 (OCHN), 173.5 and175.8 (2×C═O); m/z 370 (M+H)⁺, 100%!, 369 (M⁺), 28!, 240 39!, 215 13!and 156 11!; (Found: C, 61.98; H, 6.57; N, 3.77; C₁₉ H₂₃ NO₃ Fe requiresC, 61.80; H, 6.28; N, 3.79%). No starting ferrocenecarboxaldehyde wasdetected; were any to be present it may be removed by washing with coldpentane.

General Procedure to Form(2S,4R)-4-substituted-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-ones

1.6M n-Butyllithium (1 eq) was added dropwise to a solution intetrahydrofuran at 0° C. of diisopropylamine (1.1 eq) recently distilledfrom calcium hydride, and the mixture was stirred for 15 minutes. Theresulting solution was cooled to -78° C. and then transferred viacannula to a precooled (-78° C.) solution of the oxazolidinone fromExample 2 (1 eq) in tetrahydrofuran. Then the appropriate electrophile(1.3 eq) was added dropwise and the reaction mixture was stirredovernight while being allowed to warm up to room temperature. Thereaction mixture was concentrated on a vacuum line. Several portions ofdiethyl ether were added and then quickly passed through a sintercontaining silica and celite. The ether was removed on a vacuum line toyield title compound and the d.e. and e.e. of the major diastereomerwere determined. The product was then washed with cold pentane.

EXAMPLE 3(2S,4R)-4-Benzyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 3.0 g of the oxazolidinone from Example 2 and followingthe above general procedure using benzyl bromide as electrophile, thetitle compound (3.36 g, 90%) was obtained as yellow crystals with >98%d.e. (>98% e.e. for the main diastereomer); m.p. 159°-160° C.; R_(f)0.34 (petroleum-diethyl ether; 8:2); α!_(D) ²⁵ -191.5 (c 1.0, CHCl₃).After one crystallization the product showed α!_(D) ²⁵ -195.0 (c, 1.0,CHCl₃); V_(max) (KBr disc) 3107 (HC═C), 1790 (OC═O) and 1629 (NC═O)cm⁻¹; δ^(H) (300 MHz; CDCl₃) 0.81 (9H, s, C(CH₃)₃), 2.04 (3H, s, NCCH₃),3.21 (1H, d, J 13.5 Hz, CH_(A) H_(B)), 3.81 (1H, d, J 13.5 Hz, CH_(A)H_(B)), 4.21 and 4.25-4.26 (4H, 2 m, Cp), 4.28 (5H, s, Cp'), 6.10 (1H,s, OCHN), 7.12-7.15 and 7.24-7.28 (5H, 2 m, C₆ H₅); δ_(c) (50.3 MHz;CDCl₃) 23.6 (NCCH₃), 28.1 (C(CH₃)₃), 40.8 (C(CH₃)₃), 41.3 (CH₂), 66.2,67.9, 68.6, 68.7, 69.1, 69.3 (9×CH in Cp and Cp'), 86.7 (OCHN), 89.1(NCCH₃), 176.1 and 176.6 (2×C═O); m/z 460 (M+H)⁺, 100%)!, 459 (M⁺), 33!,331 21!, 330 50! and 199 27!; (Found: C, 67.79; H, 6.26; N, 3.28; C₂₆H₂₉ NO₃ Fe requires C, 67.98; H, 6.36; N, 3.05%).

EXAMPLE 4(2S,4R)-4-Allyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 2.135 g of the oxazolidinone from Example 2 and followingthe above general procedure using distilled allyl bromide aselectrophile, the title compound was obtained as orange crystals (1.843g, 78%) with >95% d.e. (>96% e.e. for the major diastereomer); R_(f)0.82 (petroleum-diethyl ether; 5:5); m.p. 167°-169° C.; α!²⁵ _(D) -218.2(c 1.0, CHCl₃);ν_(max) (KBr disc) 3090 m (C--H), 1795 s (OC═O), 1651 s(NC═O), 1353 s and 1186 s cm⁻¹ ; δ_(H) (300 MHz; CDCl₃) 1.05 (9H, s,C(CH₃)₃), 1.92 (3H, s, NCCH₃), 2.53 (1H, dd, J 4 Hz, 9.5 Hz, CH_(A)H_(B) --CH), 3.36 (1H, dd, J 6 Hz, 9.5 Hz, CH_(A) H_(B) --CH), 4.20-4.24and 4.28-4.32 (4H, 2 m, Cp), 4.23 (5H, s, Cp'), 5.10 (1H, s, CH═CH_(A)H_(B)), 5.15 (1H, d, J 2.5 Hz, CH═CH_(A) H_(B)), 5.47-5.61 (1H, m, CH₂--CH═CH₂ and 6.66 (1H, s, OCHN); δ_(c) (50.3 MHz; CDCl₃) 22.87 (NCCH₃),28.68 (C(CH₃)₃), 39.57 (CH₂ CH═CH₂), 41.09 (C(CH₃)₃), 64.71 (NCCH₃),67.41, 68.08, 69.05 and 69.20 (9×CH in Cp and Cp'), 86.51 (OCHN), 89.77(quaternary C in Cp), 120.04 (CH₂ --CH═CH₂), 131.62 (CH₂ --CH═CH₂),175.47 and 175.99 (2×C═O); m/z (electron ionisation) 410 (M+H)⁺, 13%!,409 (M)⁺, 73!, 121 57! and 57 (C₄ H₉)⁺, 100!; (Found C 64.53, H 6.87, N3.36; C₂₂ H₂₇ NO₃ Fe requires C 64.56, H 6.65, N 3.42%).

EXAMPLE 5(2S,4R)-4-Crotyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 226.8 mg of the oxazolidinone from Example 2 and followingthe above general procedure using distilled crotyl bromide aselectrophile, the title compound was obtained; δ_(H) (200 MHZ; CDCl₃)1.06 (9H, s, C(CH₃)₃), 1.64 (3H, d, J 6.5 Hz, CH═CHCH₃), 1.89 (3H, s,NCCH₃), 2.45 (1H, dd, J 6 Hz, 13.5 Hz, CH_(A) H_(B)), 3.28 (1H dd, J 10Hz,13.5 Hz, CH_(A) H_(B)), 4.18-4.36 (4H, m, Cp), 4.27 (5H, s, Cp'),5.06-5.24 (1H, m, CH₂ CH═CHCH₃), 5.52 (1H, dd, J 6.5 Hz, 15.5 Hz, CH₂CH═CHCH₃) and 6.64 (1H, s, OCHN).

EXAMPLE 6(2S,4R)-4-(2-Methylbenzyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 2.088 g of the oxazolidinone from Example 2 and followingthe above general procedure using α-bromo-o-xylene as electrophile, thetitle compound was obtained as yellow crystals (2.379 g, 89%) with >96%d.e. (>84% e.e. for the major diastereomer); m.p. 155°-157° C.; α!²³_(D) -180.1 (c 1.1, CHCl₃); ν_(max) (KBr disc) 2970 m (C--H), 1790 s(OC═O), 1627 s (NC═O), 1336 s and 1177 s cm⁻¹ ; δ_(H) (200 MHz; CDCl₃)0.72 (9H, s, (CH₃)₃), 2.08 (3H, s, NCCH₃), 2.36 (3H, s, C₆ H₄ CH₃), 3.28(1H, d, J 14.5 Hz, CH_(A) H_(B)), 3.82 (1H, d, J 14.5 Hz, CH_(A) H_(B)),4.21-4.32 (4H, m, Cp), 4.29 (5H, s, Cp'), 6.33 (1H, s, OCHN) and7.02-7.13 (4H, m, C₆ H₄ CH₃); δ_(c) (50.3 MHz; CDCl₃) 19.63 and 24.28(2×CH₃), 27.86 (C(CH₃)₃), 37.55 (CH₂), 40.85 (C(CH₃)₃), 65.16 (NCCH₃),67.78, 68.79, 68.94 and 69.31 (9×CH in Cp and Cp'), 86.93 (OCHN), 89.58(quaternary C in Cp), 125.88, 126.93, 128.53 and 131.22 (4×CH in C₆ H₄),134.93 and 138.18 (2×quaternary C in C₆ H₄), 176.64 and 176.71 (2×C═O);m/z (chemical ionisation, NH₃) 474 (M+H)⁺, 100%! and 344 26!; (Found C68.77, H 6.80, N 2.80; C₂₇ H₃₁ NO₃ Fe requires C 68.51, H 6.60, N2.96%).

EXAMPLE 7(2S,4R)-4-Cinnamyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 174.9 mg of the oxazolidinone from Example 2 and followingthe above general procedure using distilled cinnamyl bromide aselectrophile, the title compound was obtained; δ_(H) (200 MHz; CDCl₃)1.00 (9H, s, C(CH₃)₃), 1.97 (3H, s, NCCH₃), 2.70 (1H, dd, J 6 Hz, 14 Hz,CH_(A) H_(B)), 3.53 (1H, dd, J 9 Hz, 14 Hz, CH_(A) H_(B)), 4.19-4.34(4H, m, Cp), 4.28 (5H, s, Cp'), 5.93 (1H, ddd, J 6 Hz, 9 Hz, 15.5 Hz,CH₂ CH═CHPh), 6.45 (1H, d, J 15.5 Hz, CH₂ CH═CHPh), 6.64 (1H, s, OCHN),7.22-7.39 (5H, m, C₆ H₅).

EXAMPLE 8(2S,4R)-4-(Naphth-2-ylmethyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 126.3 g of the oxazolidinone from Example 2 and followingthe above general procedure using 2-(bromomethyl)naphthalene aselectrophile in solution in tetrahydrofuran (prepared by dissolving theelectrophile in dichloromethane, adding tetrahydrofuran and removing thedichloromethane in vacuo), the title compound was obtained as paleorange crystals (166.2 g, 95%) with >98% d.e. (>88% e.e. for the majordiastereomer); m.p. 155°-158° C.; α!²³ _(D) -49.6 (c 1.1, CHCl₃);ν_(max) (KBr disc) 2979 w (C--H), 1783 s (OC═O), 1647 m (NC═O), 1348 m,1248 m and 1172 m cm⁻¹ ; δ_(H) (200 MHz; CDCl₃) 0.79 (9H, s, C(CH₃)₃),2.10 (3H, s, NCCH₃), 3.36 (1H, d, J 13.5 Hz, CH_(A) H_(B)), 4.02 (1H, d,J 13.5 Hz, CH_(A) H_(B)), 4.22-4.25 and 4.30 (4H, 2 m, Cp,), 4.27 (5H,s, Cp'), 6.02 (1H, s, OCHN), 7.26-7.31, 7.45-7.50, 7.61 and 7.76-7.85(7H, m, C₁₀ H₇); δ_(c) (50.3 MHz; CDCl₃) 23.63 (NCCH₃), 28.01 (C(CH₃)₃),40.85 (C(CH₃)₃), 41.33 (CH₂), 66.50 (NCCH₃), 67.96, 68.67, 69.24 and69.33 (9×CH in Cp and Cp'), 86.82 (OCHN), 89.03 (quaternary C in Cp),125.93, 126.31, 127.80, 127.90, 128.16 and 129.06 (7×CH in naphthalene),132.75, 133.48 and 133.80 (3×quaternary C in naphthalene), 176.02 and176.79 (2×C═O); m/z (chemical ionisation, NH₃) 510 (M+H)⁺, 100%!, 10263! and 85 (61); (Found C 70.75, H 6.49, N 2.93; C₃₀ H₃₁ NO₃ Fe requiresC 70.73, H 6.13, N 2.75%).

EXAMPLE 9(2S,4R)-4-(1-t-Butyloxycarbonylindol-3-ylmethyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 1.310 g of the oxazolidinone from Example 2 and followingthe general procedure using 1-(t-butyloxycarbonyl)-3-(bromomethyl)indoleU. Schoellkopf, R. Lonsky, P. Lehr Liebigs Ann. Chem. 1985, 413! insolution in tetrahydrofuran as electrophile, the title compound wasobtained (1.741 g, 82%); δ_(H) (200 MHz; CDCl₃) 0.83 (9H, s, COC(CH₃)₃),1.67 (9H, s, CO₂ C(CH₃)₃), 2.10 (3H, s, NCCH₃), 3.31 (1H, d, J 14.5 Hz,CH_(A) H_(B)), 4.02 (1H, d, J 14.5 Hz, CH_(A) H_(B)), 4.16-4.27 (4H, m,Cp), 4.25 (5H, s, Cp'), 6.20 (1H s, OCHN), 7.25-7.37, 7.62-7.70 and8.15-8.18 (5H, 3 m, C₈ H₅ N).

EXAMPLE 10(2S,4R)-4-Cyanomethyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one

Starting with 224.1mg of the oxazolidinone from Example 2 and followingthe above general procedure using bromoacetonitrile as electrophile, thetitle compound was obtained; δ_(H) (200 MHz; CDCl₃), 1.12 (9H, s,C(CH₃)₃), 1.93 (3H, NCCH₃), 2.89 (1H, d, J 16.5 Hz, CH_(A) H_(B)), 3.83(1H, d, J 16.5 Hz, CH_(A) H_(B)), 4.18-4.29 (4H, m, Cp), 4.28 (5H, s,Cp') and 6.88 (1H, s, OCHN).

General Hydrolysis Procedure to Form Free Amino Acid

A glass column was filled with distilled water and Amberlyst-15 wasadded slowly and in several portions into the column. It was washed withdistilled water up to pH 3 and then with acetone-distilled water (9:1).The substituted oxazolidinone was dissolved in acetone-distilled water(9:1); a gentle warming was sometimes needed to complete dissolution.The resulting solution was poured into the column and left overnight.Elution with acetone-distilled water (9:1), removal of the acetone invacuo, followed by extraction of the aqueous solution with diethyl etherand purification by column chromatography (silicagel-petroleum ether;90:20) yielded ferrocenecarboxaldehyde. The column was then eluted with2% ammonium hydroxide. The aqueous solution was concentrated in vacuo toyield free amino acid.

EXAMPLE 11 (R)-(+)-α-Methylphenylalanine

Starting with 3.0 g of(2S,4R)-4-benzyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-onefrom Example 3 and following the above general hydrolysis procedure,ferrocenecarboxaldehyde (0.89 g, 76%) and free amino acid were obtained.The latter was dissolved in methanol and passed through a sintercontaining decolourising charcoal to yield, after removing the solvent,the title compound (0.89 g, 76%) as colourless crystals; α!₅₇₈ ²⁵ +17 (c0.1, MeOH) F. W. Bollinger J. Med. Chem. 1971, 14, 373 and D. Seebach,A. Fadel Helv. Chim. Acta 1985, 68, 1243 give m.p. 307°-308° C. dec. andα!₅₇₈ ²⁴ +20 (c 0.1 MeOH)!. This product proved difficult to dehydrate,showed a tendency to rehydrate, and was easily oxidisable by air. Thecorresponding hydrochloride was prepared as described by Bollinger (op.cit.); ν_(max) (KBr disc) 3436 (N--H), 3034 (HC═C), 1619 (CO₂ ⁻) and1583 (C═C) cm⁻¹ ; δ_(H) (200 MHz; CH₃ OD) 1.50 (3H, S, CH₃), 2.92 (1H,d, J 14 Hz, CH_(A) H_(B)), 3.28 (1H, d, J 14 Hz, CH_(A) H_(B)) and 7.29(5H, m, C₆ H₅); δ_(c) (50.3 MHz, CH₃ OD) 21.5 (CH₃), 42.6 (CH₂), 60.7(CCH₃), 127.6, 128.7, 130.2, 134.1 (5×CCH in C₆ H₅) and 173.9 (C═O); m/z180 (M+H)⁺, 100%!, 134 16! and 88 21!; (Found: C, 55.86; H, 6.77; N,6.72; C₁₀ H₁₄ NO₂ Cl requires C, 55.69; H, 6.54; N, 6.49%)

EXAMPLE 12 (R)-(+)-α-Methylallylalanine

Starting with 1.843 g of(2S,4R)-4-allyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-onefrom Example 4 and following the above general hydrolysis procedure,ferrocenecarboxaldehyde (0.815 g, 85%) and free amino acid wereobtained. The latter was dissolved in methanol and passed through asinter containing decolourising charcoal to yield, after removing thesolvent, the title compound as colourless crystals (0.555 g, 95%); m.p.296°-299° C.; α!²⁵ _(D) +24.1 (c 0.7, MeOH); α!²² _(D) +6.1 (c 1.3, D₂O); ν_(max) (KBr disc) 3021 s br (OCO--H), 1645 s (C═O), 1575 s and 1545s cm⁻¹ ; δ_(H) (200 MHz; D₂ O) 1.47 (3H, s, CH₃), 2.43 (1H, dd, J 8 Hz,14.5 Hz, CH_(A) H_(B)), 2.65 (1H, dd, J 6.5 Hz, 14.5 Hz, CH_(A) H_(B)),5.22 (1H, d, J 4 Hz, CH═CH₂), 5.28 (1H, s, CH═CH₂) and 5.63-5.84 (1H, m,CH═CH₂); δ_(c) (50.3 MHz, CH₂ OD) 21.40 (CH₃), 41.49 (CH₂ CH═CH₂), 59.96(CCH₃), 120.05 (CH₂ CH═C₂) and 131.20 (CH₂ CH═CH₂); m/z (desorptionchemical ionisation, NH₃) 130 (M+H)⁺, 100%!, 88 21! and 84 17!.

EXAMPLE 13 (R)-(+)-α-methyl-(2-methylbenzyl)alanine

Starting with(2S,4R)-4-(2-methylbenzyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-onefrom Example 6 and following the above general hydrolysis procedure,ferrocenecarboxaldehyde and the title compound were obtained; δ_(H) (200MHz; D₂ O) 1.30 and 2.09 (2×3H, 2×s, CH₃), 2.91 (1H, d, J 14.5 Hz,CH_(A) H_(B)), 3.02 (1H, d, J 14.5 Hz, CH_(A) H_(B)) and 6.96-7.04 (4H,m, C₆ H₄).

We claim:
 1. Chiral compounds of formula (V) ##STR7## where R represents a hydrogen atom or an organic group selected from the group consisting of optionally substituted aliphatic, cycloaliphatic and araliphatic groups containing up to 20 carbon atoms; R¹ represents an N-protecting group; R² represents an organic group selected from the group consisting of optionally substituted aliphatic and araliphatic groups containing up to 20 carbon atoms; R^(a) and R^(b), which may be the same or different, are each selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, disubstituted amino, disubstituted aminoalkyl, lower alkanoylamino, C₆₋₁₂ aryl-C₁₋₄ alkyl, C₆₋₂₀ aryl, carbamoyl, sulphamoyl, nitro and halo, or R^(b) is an oxazolidinone group of formula: ##STR8## m is 0 or an integer of 1-4; n is 0 or an integer of 1-5; and the asterisk denotes that the configuration of R and R² is such that the compound is in substantially enantiomerically pure form.
 2. Compounds as claimed in claim 1 wherein R is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, optionally protected hydroxymethyl, optionally protected 1-hydroxyethyl, optionally protected mercaptomethyl, optionally protected carboxymethyl, optionally protected 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(methylthio)ethyl, optionally protected 4-aminobutyl, benzyl, optionally protected p-hydroxybenzyl, optionally protected indol-3-ylmethyl, optionally protected imidazol-4-ylmethyl, and optionally protected 3-guanidinopropyl.
 3. Compounds as claimed in claim 1 wherein R¹ is a lower alkanoyl, lower alkoxycarbonyl, lower alkylsuphonyl, aryl sulphonyl, tri(lower alkyl)silyl, camphanyl or camphasulphonyl group.
 4. Compounds as claimed in claim 1 wherein R² is an optionally substituted lower alkyl, lower alkenyl, carbocyclic or heterocyclic aryl lower alkyl or carbocyclic or heterocyclic aryl lower alkenyl group.
 5. Compounds as claimed in claim 4 wherein R² represents a cyanomethyl, allyl, crotyl, benzyl, 2-methylbenzyl, naphth-2-ylmethyl, N-protected indol-3-ylmethyl or cinnamyl group.
 6. Compounds as claimed in claim 2 wherein m and n are both
 0. 7. Compounds as claimed in claim 1 wherein m is 1 and the substituent R^(a) is positioned ortho to the 1,3-oxazolidin-5-one ring.
 8. Compounds as claimed in claim 1 wherein n is at least 1 and at least one R^(b) substituent is a group of formula ##STR9## where R, R¹, R² and the meaning of the asterisk are as defined in claim
 1. 9. The compounds:(2S,4R)-4-benzyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-allyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-crotyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-(2-methylbenzyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-cinnamyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-(naphth-2-ylmethyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; (2S,4R)-4-(1-t-butoxycarbonylindol-3-ylmethyl)-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one; and (2S,4R)-4-cyanomethyl-2-ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one.
 10. Chiral compounds of formula (IV) ##STR10## where R represents a hydrogen atom or an organic group selected from the group consisting of optionally substituted aliphatic, cycloaliphatic and araliphatic groups containing up to 20 carbon atoms; R¹ represents an N-protecting group: R^(a) and R^(b), which may be the same or different, are each selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, disubstituted amino, disubstituted aminoalkyl, lower alkanoylamino. C₆₋₁₂ aryl-C₁₋₄ alkyl, C₆₋₂₀ aryl, carbamoyl, sulphamoyl, nitro and halo, or at least one of R^(b) is an oxazolidinone group of formula: ##STR11## m is 0 or an integer of 1-4; and n is 0 or an integer of 1-5.
 11. Compounds as claimed in claim 10 wherein R is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, optionally substituted hydroxymethyl, optionally substituted 1-hydroxyethyl, optionally substituted mercaptomethyl, optionally substituted carboxymethyl, optionally substituted 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(methylthio)ethyl, optionally substituted 4-aminobutyl, benzyl, optionally substituted p-hydroxybenzyl, optionally substituted indol-3-ylmethyl, optionally substituted imidazol-4-ylmethyl, and optionally substituted 3-guanidinopropyl.
 12. Compounds as claimed in claim 10 wherein R¹ is a lower alkanoyl, lower alkoxycarbonyl, lower alkylsulphonyl, aryl sulphonyl, tri(lower alkyl)silyl, camphanyl or camphasulphonyl group.
 13. Compounds as claimed in any of claim 10 wherein m and n are both
 0. 14. Compounds as claimed in claim 10 wherein m is 1 and the substituent R^(a) is positioned ortho to the 1,3-oxazolidin-5-one ring.
 15. Compounds as claimed in claim 10 wherein n is at least 1 and at least one R^(b) substituent is a group of formula ##STR12## where R and R¹ are as defined in claim
 1. 16. (2S,4S)-4-Ferrocenyl-4-methyl-3-pivaloyl-1,3-oxazolidin-5-one.
 17. A process for the preparation of a chiral compound of formula (IV) as claimed in claim 10 wherein an α-amino acid or salt of formula (I) ##STR13## wherein R is as defined in claim 10 and X represents a hydrogen atom or a cation is reacted with a compound of formula (II) ##STR14## wherein R^(a), R^(b), m and n are as defined in claim 10 to yield a Schiff's base of formula (III) ##STR15## wherein R, R^(a),R^(b), m and n are as defined in claim 10 and X is as defined in this claim and said compound (III) is reacted with a compound serving to introduce an N-protecting group at the imine nitrogen atom to yield said compound of formula (IV).
 18. Ferrocene carboxaldehyde sodium L-alaninate imine.
 19. A process for the preparation of a compound of formula (V) as claimed in claim 2 wherein a compound of formula (IV) ##STR16## where R represents a hydrogen atom or an organic group selected from the group consisting of optionally substituted aliphatic, cycloaliphatic and araliphatic groups containing up to 20 carbon atoms; R¹ represents an N-protecting group; R^(a) and R^(b), which may be the same or different, are each selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulphonyl, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, disubstituted amino, disubstituted aminoalkyl, lower alkanoylamino, C₆₋₁₂ aryl-C₁₋₄ 0 alkyl, C₆₋₂₀ aryl, carbamoyl, sulphamoyl, nitro and halo, or R^(b) is an oxazolidinone group of formula; ##STR17## m is 0 or an integer of 1-4; and n is 0 or an integer of 1-5, is subjected to electrophilic substitution to yield said compound of formula (V). 